New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

// Muhammad Altaf 1 , Muhammad Monim-ul-Mehboob 2 , Abdel-Nasser Kawde 2 , Giuseppe Corona 3 , Roberto Larcher 4 , Marcia Ogasawara 5 , Naike Casagrande 6 , Marta Celegato 6 , Cinzia Borghese 6 , Zahid H. Siddik 5 , Donatella Aldinucci 6 , Anvarhusein A. Isab 2 1 Center of Excellence in Nanotechnology (CENT), King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia 2 Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia 3 Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, PN, Italy 4 Center for Technological Transfer, Edmund Mach Foundation, Trento, Italy 5 The University of Texas MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, Texas, USA 6 Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, PN, Italy Correspondence to: Donatella Aldinucci, email: daldinucci@cro.it Anvarhusein A. Isab, email: aisab@kfupm.edu.sa Zahid H. Siddik, email: zsiddik@mdanderson.org Keywords: gold(III) complexes, bipyridine, cisplatin resistance, reactive oxygen species, p53 Received: June 17, 2016      Accepted: November 12, 2016      Published: November 18, 2016 ABSTRACT We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC 50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.